This proposal describes a 5-year training program that will expand the applicant's scientific knowledge, advance her expertise in patient-oriented translational research, and establish independence from her primary mentor. A 4-member Mentoring Team and 3-member Advisory Committee will oversee her training and career development. The current application represents a patient-oriented clinical proposal that examines mechanisms of obesity-associated insulin resistance in human subjects. Obesity has emerged as one of the most critical health care problems in the US. Adipose tissue dysfunction and inflammation are essential hallmarks linking obesity to the pathogenesis of cardiometabolic disease. The proposal will employ a number of complementary approaches harnessing physiological studies of vascular endothelial function, pharmacological and biological methods to probe dysfunctional insulin signaling pathways in fat tissue, immunohistochemical techniques for adipose phenotyping, and computed tomography (CT) imaging of human fat to gain novel insight into pathogenic disease mechanisms. In aim 1, she will examine insulin-mediated vasodilator responses using videomicroscopy of arterioles isolated from subcutaneous and two separate visceral adipose depots biopsied during planned bariatric surgery in 200 obese subjects, and probe the functional significance of Wnt-pathway signaling in the regulation of vascular insulin resistance. Aim 2 will utilize abdominal CT imaging to identify quantitative and qualitative depot-specific adipose tissue parameters linked to insulin resistance and vascular dysfunction. CT findings will be compared to the histoarchitecture of adipose tissue samples biopsied in aim 1 that will provide a defined basis for correlating imaging study findings with histopathological and molecular processes at the tissue level that may provide novel clues to disease mechanisms. Aim 3 will repeat studies of vascular endothelial function, metabolic profiling, CT imaging and adipose tissue biopsies 6-months after bariatric surgical intervention in the same 200 obese subjects from aim 1. The applicant will examine how relevant and interlinked relationships that govern insulin resistance and vascular dysfunction identified in aims 1 and 2 are influenced by marked weight reduction in severely obese individuals where very little information currently exists. The long-term goal of the applicant is to develop an academic career as a clinical scientist in the field of obesity and cardiovascular disease. This proposal will allow the applicant to expand her translational research expertise and mature her patient-oriented research in an area that is relatively unexplored and medically important. Obesity will remain one of the most important health care challenges worldwide, and improving our understanding of mechanisms of obesity-related cardiovascular disease is critical.